tbuckley/cabot-search huggingface dataset:
PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors
Authors: Amanda L. Gill, Peter H. Wang, Judong Lee, William H. Hudson, Satomi Ando, Koichi Araki, Yinghong Hu, Andreas Wieland, Sejin Im, Autumn Gavora, Christopher B. Medina, Gordon J. Freeman, Masao Hashimoto, Steven L. Reiner, Rafi Ahmed
Journal: Science Immunology (2023)

PD-1 + TCF-1 + stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)–directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases. To investigate this, we used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Treatment of chronically infected mice with either αPD-1 or αPD-L1 antibody not only increased effector cell differentiation from the virus-specific stem-like CD8 T cells but also increased their proliferation so their numbers were maintained. The increased self-renewal of LCMV-specific stem-like CD8 T cells was mTOR dependent. We used microscopy to understand the division of these progenitor cells and found that after PD-1 blockade, an individual dividing cell could give rise to a differentiated TCF-1 − daughter cell alongside a self-renewing TCF-1 + sister cell. This asymmetric division helped to preserve the number of stem-like cells. Moreover, we found that the PD-1 + TCF-1 + stem-like CD8 T cells retained their transcriptional program and their in vivo functionality in terms of responding to viral infection and to repeat PD-1 blockade. Together, our results demonstrate that PD-1 blockade does not deplete the stem-like population despite increasing effector differentiation. These findings have implications for PD-1–directed immunotherapy in humans.
Sonodynamic amplification of cGAS-STING activation by cobalt-based nanoagonist against bone and metastatic tumor
Authors: Jie Lei, Weifeng Zhang, Liang Ma, Yaqi He, Huaizhen Liang, Xiaoguang Zhang, Gaocai Li, Xiaobo Feng, Lei Tan, Cao Yang
Journal: Biomaterials (2023)
Altered Notch signalling in Dowling-Degos disease: a transcriptomic insight into disease pathogenesis
Authors: Sheetal Kumar, Jonas Hausen, Sugirthan Sivalingam, Aytaj Humbatova, Andreas Buness, Jorge Frank, Damian J Ralser, Regina C Betz
Journal: British Journal of Dermatology (2023)

Dowling-Degos disease (DDD) is a rare autosomal-dominant hyperpigmentation disorder caused by mutations in KRT5, POFUT1, POGLUT1 and PSENEN. Our results suggest that dysfunctional Notch signalling in melanocytes plays a key role in DDD pathogenesis, and that altered biogenesis and intracellular trafficking of melanosomes, receptor tyrosine kinase signalling and oestrogen signalling receptor-mediated signalling may represent downstream molecular mechanisms through which decreased Notch signalling leads to hyperpigmentation in DDD. Furthermore, a common downstream pathomechanism for both POGLUT1 and PSENEN mutation carriers can be assumed.
Nucleus Pulposus‐Targeting Nanocarriers Facilitate Mirna‐Based Therapeutics for Intervertebral Disc Degeneration
Authors: Zhonghui Chen, Zhong Liao, Ming Liu, Fengfei Lin, Shunyou Chen, Geng Wang, Zhong Zheng, Boling Liu, Chaoxiong Li, Zheqiang Wang, Tianlai Chen, Hongzhe Huang, Qi Liao, Weiliang Cui
Journal: Advanced Healthcare Materials (2023)

Intervertebral disc degeneration (IDD) is a common cause of low back pain. Understanding its molecular mechanisms is the basis for developing specific treatment. To demonstrate that miR-22-3p is critical in the regulation of IDD, miRNA microarray analyses are conducted in conjunction with in vivo and in vitro experiments. The miR-22-3p knockout (KO) mice show a marked decrease in the histological scores. Bioinformatic analysis reveals that miR-22-3p plays a mechanistic role in the development of IDD by targeting SIRT1, which in turn activates the JAK1/STAT3 signaling pathway. This is confirmed by a luciferase reporter assay and western blot analysis. Therapeutically, the delivery of miR-22-3p inhibitors and mimics through the synthesized nanoparticles in the IDD model alleviates and aggravates IDD, respectively. The nanocarriers enhance transportation of miR-22-3p to nucleus pulposus cells, thus enabling the in vivo inhibition of miR-22-3p for therapeutic purposes and consequently promoting the development of miRNA-specific drugs for IDD.
Towards the development of a SARS-CoV-2 variant risk assessment tool: expert consultation on the assessment of scientific evidence on emerging variants
Authors: Nathalie Worp, Lorenzo Subissi, Mark D Perkins, Maria D Van Kerkhove, Anurag Agrawal, Meera Chand, Janko van Beek, Bas B Oude Munnink, Marion P G Koopmans
Journal: The Lancet Microbe (2023)

<h2>Summary</h2> A systematic approach is required for the development of an evidence-based risk assessment tool to robustly estimate the risks and implications of SARS-CoV-2 variants. We conducted a survey among experts involved in technical advisory roles for WHO to capture their assessment of the robustness of different study types that provide evidence for potential changes in transmissibility, antigenicity, virulence, treatability, and detectability of SARS-CoV-2 variants. The views of 62 experts indicated that studies could be grouped on the basis of robustness and reliability for the different risk indicators mentioned. Several study types that experts scored as providing reliable evidence and that can be performed in a timely manner were identified. Although experts from different technical areas had varying responses, there was agreement on the highest and lowest scoring study types. These findings can help to prioritise, harmonise, and optimise study designs for the further development of a systematic, evidence-based, SARS-CoV-2 variant risk assessment tool.
Age at Type 2 Diabetes Diagnosis and Cause-Specific Mortality: Observational Study of Primary Care Patients in England
Authors: Mary M. Barker, Melanie J. Davies, Jack A. Sargeant, Juliana C.N. Chan, Edward W. Gregg, Sharmin Shabnam, Kamlesh Khunti, Francesco Zaccardi
Journal: Diabetes Care (2023)

OBJECTIVE To examine the associations between age at type 2 diabetes diagnosis and the relative and absolute risk of all-cause and cause-specific mortality in England. RESEARCH DESIGN AND METHODS In this cohort study using primary care data from the Clinical Practice Research Datalink, we identified 108,061 individuals with newly diagnosed type 2 diabetes (16–50 years of age), matched to 829,946 individuals without type 2 diabetes. We estimated all-cause and cause-specific mortality (cancer, cardiorenal, other [noncancer or cardiorenal]) by age at diagnosis, using competing-risk survival analyses adjusted for key confounders. RESULTS Comparing individuals with versus without type 2 diabetes, the relative risk of death decreased with an older age at diagnosis: the hazard ratio for all-cause mortality was 4.32 (95% CI 3.35–5.58) in individuals diagnosed at ages 16–27 years compared with 1.53 (95% CI 1.46–1.60) at ages 48–50 years. Smaller relative risks by increasing age at diagnosis were also observed for cancer, cardiorenal, and noncancer or cardiorenal death. Irrespective of age at diagnosis, the 10-year absolute risk of all-cause and cause-specific mortality were higher in individuals with type 2 diabetes; yet, the absolute differences were small. CONCLUSIONS Although the relative risk of death in individuals with versus without type 2 was higher at younger ages, the 10-year absolute risk of all investigated causes of death was small and similar in the two groups. Further multidecade studies could help estimate the long-term risk of complications and death in individuals with early-onset type 2 diabetes.
Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis
Authors: Wen-Juei Jeng, Rong-Nan Chien, Yi-Cheng Chen, Chih-Lang Lin, Chia-Ying Wu, Yen-Chun Liu, Chien-Wei Peng, Chung-Wei Su, Cheng-Er Hsu, Yun-Fan Liaw
Journal: Hepatology (2023)

Background and Aims: Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. Approach and Results: From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4–8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p &lt;0.0001). The finite group showed greater HBsAg decline/year (−0.116 vs. −0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p &lt;0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). Conclusions: Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.
Addressing homelessness after prison release
Authors: Lars Højsgaard Andersen
Journal: The Lancet Public Health (2023)

People who are released from prison face challenges with social reintegration,1 and securing suitable housing constitutes a particularly important issue, which might be associated with recidivism risk.2 After release from prison, many people might end up with unstable housing, reside with family or friends, or in temporary shelters.3–5 The links between imprisonment, homelessness or unstable housing, and the risk of recidivism are complex; in The Lancet Public Health, Sandra Nilsson and colleagues make an important contribution to this area of research, using high quality nationwide, register-based data from Denmark.
UNesT: Local spatial representation learning with hierarchical transformer for efficient medical segmentation
Authors: Xin Yu, Qi Yang, Yinchi Zhou, Leon Y. Cai, Riqiang Gao, Ho Hin Lee, Thomas Li, Shunxing Bao, Zhoubing Xu, Thomas A. Lasko, Richard G. Abramson, Zizhao Zhang, Yuankai Huo, Bennett A. Landman, Yucheng Tang
Journal: Medical Image Analysis (2023)
Uganda’s anti-homosexuality act is causing harm and limiting access to healthcare
Authors: Stellah Bosire
Journal: BMJ (2023)

This week, four people were arrested by Ugandan police for allegedly engaging in same sex activity. 1 This oppressive environment follows the introduction of the Anti-Homosexuality Act, known as one of the world's most draconian anti-LGBTQ+ laws. 2 As a result, many members of the LGBTQ+ community are forced to conceal their identities because of the fear of identification, arbitrary arrest, and prosecution based on their real or perceived sexual orientation or gender identity.
Author Correction: Somatic mutations in facial skin from countries of contrasting skin cancer risk
Authors: Charlotte King, Joanna C. Fowler, Irina Abnizova, Roshan K. Sood, Michael W. J. Hall, Ildikó Szeverényi, Muly Tham, Jingxiang Huang, Stephanie Ming Young, Benjamin A. Hall, E. Birgitte Lane, Philip H. Jones
Journal: Nature Genetics (2023)
Translation dysregulation in neurodegenerative diseases: a focus on ALS
Authors: Shaopeng Wang, Shuying Sun
Journal: Molecular Neurodegeneration (2023)

Abstract RNA translation is tightly controlled in eukaryotic cells to regulate gene expression and maintain proteome homeostasis. RNA binding proteins, translation factors, and cell signaling pathways all modulate the translation process. Defective translation is involved in multiple neurological diseases including amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder and poses a major public health challenge worldwide. Over the past few years, tremendous advances have been made in the understanding of the genetics and pathogenesis of ALS. Dysfunction of RNA metabolisms, including RNA translation, has been closely associated with ALS. Here, we first introduce the general mechanisms of translational regulation under physiological and stress conditions and review well-known examples of translation defects in neurodegenerative diseases. We then focus on ALS-linked genes and discuss the recent progress on how translation is affected by various mutant genes and the repeat expansion-mediated non-canonical translation in ALS.
How AI can learn from the law: putting humans in the loop only on appeal
Authors: I. Glenn Cohen, Boris Babic, Sara Gerke, Qiong Xia, Theodoros Evgeniou, Klaus Wertenbroch
Journal: npj Digital Medicine (2023)

Abstract While the literature on putting a “human in the loop” in artificial intelligence (AI) and machine learning (ML) has grown significantly, limited attention has been paid to how human expertise ought to be combined with AI/ML judgments. This design question arises because of the ubiquity and quantity of algorithmic decisions being made today in the face of widespread public reluctance to forgo human expert judgment. To resolve this conflict, we propose that human expert judges be included via appeals processes for review of algorithmic decisions. Thus, the human intervenes only in a limited number of cases and only after an initial AI/ML judgment has been made. Based on an analogy with appellate processes in judiciary decision-making, we argue that this is, in many respects, a more efficient way to divide the labor between a human and a machine. Human reviewers can add more nuanced clinical, moral, or legal reasoning, and they can consider case-specific information that is not easily quantified and, as such, not available to the AI/ML at an initial stage. In doing so, the human can serve as a crucial error correction check on the AI/ML, while retaining much of the efficiency of AI/ML’s use in the decision-making process. In this paper, we develop these widely applicable arguments while focusing primarily on examples from the use of AI/ML in medicine, including organ allocation, fertility care, and hospital readmission.
Clonal Hematopoiesis Has Prognostic Value in Dilated Cardiomyopathy Independent of Age and Clone Size
Authors: Maurits A. Sikking, Sophie L.V.M. Stroeks, Michiel T.H.M. Henkens, Anne G. Raafs, Benjamin Cossins, Rosanne C. van Deuren, Marlies Steehouwer, Niels P. Riksen, Arthur van den Wijngaard, Han G. Brunner, Alexander Hoischen, Job A.J. Verdonschot, Stephane R.B. Heymans
Journal: JACC Heart Failure (2023)
Atypical fibroxanthoma and pleomorphic dermal sarcoma: Local recurrence and metastasis in a nationwide population-based cohort of 1118 patients
Authors: Mathias Ørholt, Kiya Abebe, Louise E. Rasmussen, Frederik L. Aaberg, Lærke J. Lindskov, Grethe Schmidt, Anne Lene Wagenblast, Michael M. Petersen, Anand C. Loya, Søren Daugaard, Mikkel Herly, David Hebbelstrup Jensen, Peter Vester-Glowinski
Journal: Journal of the American Academy of Dermatology (2023)

The prognosis of patients with atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) remains uncertain and no standardized follow-up programs have been established.To recommend a standardized follow-up program of patients with AFX and PDS based on nationwide long-term estimates of local recurrence and metastasis.All patients with AFX and PDS in Denmark between 2002 and 2022 were included. Danish National Registries were used to estimate the risks of local recurrence and metastasis for AFX and PDS.The 5-year risk of local recurrence was 10% for AFX and 17% for PDS. The 5-year risk of metastasis was 0.8% for AFX and 16% for PDS. PDS metastasized within 3 years in >90% of the patients with the lungs as the primary metastasis site (50%). Invasion beyond the subcutis, perineural/intravascular infiltration, and increasing age significantly increased the risk of PDS relapse.Risk of misclassification and lack of detailed surgical information.The follow-up of patients with AFX can be limited to clinical visits for 4 years. Patients with PDS should be followed with clinical visits and PET/CT twice a year for the first 3 years and once a year for a minimum of 1 year.
Single-cell resolution analysis reveals the preparation for reprogramming the fate of stem cell niche in cotton lateral meristem
Authors: Xiangqian Zhu, Zhongping Xu, Guanying Wang, Yulong Cong, Lu Yu, Ruoyu Jia, Yuan Qin, Guangyu Zhang, Bo Li, Daojun Yuan, Lili Tu, Xiyan Yang, Keith Lindsey, Xianlong Zhang, Shuangxia Jin
Journal: Genome biology (2023)

Abstract Background Somatic embryogenesis is a major process for plant regeneration. However, cell communication and the gene regulatory network responsible for cell reprogramming during somatic embryogenesis are still largely unclear. Recent advances in single-cell technologies enable us to explore the mechanism of plant regeneration at single-cell resolution. Results We generate a high-resolution single-cell transcriptomic landscape of hypocotyl tissue from the highly regenerable cotton genotype Jin668 and the recalcitrant TM-1. We identify nine putative cell clusters and 23 cluster-specific marker genes for both cultivars. We find that the primary vascular cell is the major cell type that undergoes cell fate transition in response to external stimulation. Further developmental trajectory and gene regulatory network analysis of these cell clusters reveals that a total of 41 hormone response-related genes, including LAX2 , LAX1 , and LOX3 , exhibit different expression patterns in the primary xylem and cambium region of Jin668 and TM-1. We also identify novel genes, including CSEF , PIS1 , AFB2 , ATHB2 , PLC2 , and PLT3 , that are involved in regeneration. We demonstrate that LAX2 , LAX1 and LOX3 play important roles in callus proliferation and plant regeneration by CRISPR/Cas9 editing and overexpression assay. Conclusions This study provides novel insights on the role of the regulatory network in cell fate transition and reprogramming during plant regeneration driven by somatic embryogenesis.
Divergent chondro/osteogenic transduction laws of fibrocartilage stem cell drive temporomandibular joint osteoarthritis in growing mice
Authors: Ruiye Bi, Qianli Li, Haohan Li, Peng Wang, Han Fang, Xianni Yang, Yiru Wang, Yi Hou, Binbin Ying, Songsong Zhu
Journal: International Journal of Oral Science (2023)

The anterior disc displacement (ADD) leads to temporomandibular joint osteoarthritis (TMJOA) and mandibular growth retardation in adolescents. To investigate the potential functional role of fibrocartilage stem cells (FCSCs) during the process, a surgical ADD-TMJOA mouse model was established. From 1 week after model generation, ADD mice exhibited aggravated mandibular growth retardation with osteoarthritis (OA)-like joint cartilage degeneration, manifesting with impaired chondrogenic differentiation and loss of subchondral bone homeostasis. Lineage tracing using Gli1-CreER+; Tmfl/-mice and Sox9-CreER+;Tmfl/-mice showed that ADD interfered with the chondrogenic capacity of Gli1+ FCSCs as well as osteogenic differentiation of Sox9+ lineage, mainly in the middle zone of TMJ cartilage. Then, a surgically induced disc reposition (DR) mouse model was generated. The inhibited FCSCs capacity was significantly alleviated by DR treatment in ADD mice. And both the ADD mice and adolescent ADD patients had significantly relieved OA phenotype and improved condylar growth after DR treatment. In conclusion, ADD-TMJOA leads to impaired chondrogenic progenitor capacity and osteogenesis differentiation of FCSCs lineage, resulting in cartilage degeneration and loss of subchondral bone homeostasis, finally causing TMJ growth retardation. DR at an early stage could significantly alleviate cartilage degeneration and restore TMJ cartilage growth potential.
Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents
Authors: Neeraj Jain, Mukesh Mamgain, Sayan Mullick Chowdhury, Udita Jindal, Isha Sharma, Lalit Sehgal, Narendranath Epperla
Journal: Journal of Hematology & Oncology (2023)

Abstract Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2–6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton's tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody–drug conjugates.
RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts
Authors: Gerald F. Watts, Christian Schwabe, Russell Scott, Patrick A. Gladding, David Sullivan, John Baker, Peter Clifton, James Hamilton, Bruce Given, Stacey Melquist, Rong Zhou, Ting Chang, Javier San Martin, Daniel Gaudet, Ira J. Goldberg, Joshua W. Knowles, Robert A. Hegele, Christie M. Ballantyne
Journal: Nature Medicine (2023)

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0-10.5 h and clearance from plasma within 24-48 h after dosing with a mean t½ of 3.9-6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85 days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224.